Neuropeptide Y (NPY) receptors are activated by a closely related group of peptide agonists termed “NPY family” which have differing affinities for each receptor sub-type. NPY, peptide tyrosine-tyrosine (PYY) and pancreatic polypeptide (PP), all 36 amino acids in length, are agonists for the NPY family of receptors. NPY is a neurotransmitter, synthesized, co-stored and released with norepinephrine and epinephrine. NPY is one of the most abundant and widely distributed peptides in the central nervous system (CNS) of humans and rodents and is expressed in areas of the brain related to feeding and stress. In the peripheral nervous system, NPY-containing neurons are predominantly sympathetic. PYY is predominantly synthesized and released by intestinal endocrine cells. Cleavage of NPY and PYY by the endothelial serine-protease, di-peptidyl peptidase IV (DPP-IV), generates NPY3-36 and PYY3-36 which are selective ligands for Y2 and Y5 sub-types of the NPY receptor family. PP is mainly found in pancreatic islet cells distinct from those storing insulin, glucagon or somatostatin.
Five distinct NPY receptors have been identified to date, four of which are understood as relevant to human physiology. The receptors Y1, Y2 and Y5 preferentially bind NPY and PYY, whereas the Y4 receptor preferentially binds PP. The Y2 and Y5 receptors are also potently activated by NPY3-36 and PYY3-36. In general, the NPY family of ligands possesses variable selectivity for each of the NPY receptor isoforms, with PYY3-36 previously reported to have modest-to-robust selectivity for the Y2 isoform. Each of these receptors is coupled to inhibition of adenylate cyclase via pertussis-toxin sensitive Gαi.
PYY is secreted from endocrine L-cells in response to food, and in particular following fat ingestion. PYY1-36 predominates in the fasting state, with PYY3-36 being the major form found post-prandially in humans, with plasma concentrations negatively correlated with the number of calories consumed. PYY3-36 has been demonstrated to reduce food intake in humans, monkeys, rats, rabbits, and mice (Batterham R L et al. Nature 2002 Aug. 8; 418(6898):650-4; Batterham R L et al. N Engl J Med 2003 Sep. 4; 349(10):941-8; Challis B G et al., Biochem Biophys Res Commun 2003 Nov. 28; 311(4):915-9). The anorexigenic effects of PYY3-36 are believed to be Y2-mediated, based on preferential binding at this receptor and loss of feeding efficacy in Y2-deficient mice (Batterham R L, et al. Nature 2002 Aug. 8; 418(6898):650-4). Intra-arcuate injection of PYY3-36 reduces food intake in rats and mice (Batterham et al. Nature 2002 Aug. 8; 418(6898):650-4), suggesting that engagement of hypothalamic Y2 receptors may mediate these effects. Acute effects on feeding have also been shown to translate to dose-dependent effects on body-weight in ob/ob mice, DIO mice and Zucker fa/fa mice (Pittner R A et al. Int J Obes relat Metab Disord 2004 August; 28(8):963-71). In addition, PYY3-36 has also been shown to improve insulin-mediated glucose disposal and insulin sensitivity in DIO rodents (Vrang N et al., Am J Physiol Regul Integr Comp Physiol August; 291(2):R367-75). Bariatric surgery results in increased circulating PYY-immunoreactivity (le Roux C W et al., Ann Surg 2006 January; 243(1); 108-14), which appears to play a role in postoperative weight loss.
Given its role in controlling appetite and food intake as well as its anti-secretory and pro-absorptive effects in the gastrointestinal tract in mammals, PYY3-36 may be effective in treating obesity and associated conditions as well as in a number of gastrointestinal disorders. However, the therapeutic utility of PYY3-36 itself as a treatment agent is limited by its rapid metabolism and resultant short circulating half-life (Torang et al., Am. J. Physiol. Regul. Integr. Comp. Physiol. 310:R866-R874 (2016)).
Thus, it is desirable to obtain a PYY analogue or derivative thereof with an improved metabolic stability and pharmacokinetic profile relative to PYY3-36. Such derivatives, with a protracted half-life in vivo, would provide Y2 receptor modulation with greater duration of action, making them suitable as therapeutic agents for subjects in need of such modulation.
The foregoing discussion is presented solely to provide a better understanding of the nature of the problems confronting the art and should not be construed in any way as an admission as to prior art nor should the citation of any reference herein be construed as an admission that such reference constitutes “prior art” to the instant application.